Hypoxia inducible factor (HIF) is a basic helix-loop-helix (bHLH) PAS (Per/Arnt/Sim) transcriptional activator that regulates changes in gene expression in response to changes in cellular oxygen concentration. HIF is a heterodimer containing an oxygen-regulated alpha subunit (HIFα) and a constitutively expressed beta subunit (HIFβ), also known as the aromatic hydrocarbon receptor nuclear transporter (ARNT). In oxygenated (normoxic) cells, the HIFα subunit is rapidly degraded by a mechanism involving the ubiquitination of the VonHipple-Lindau tumor suppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIFα does not degrade, and an active HIFα/β complex accumulates in the nucleus and activates expression of several genes, including glycolytic enzymes, glucose transporter (GLUT)-1, erythropoietin (EPO) and vascular endothelial growth factor (VEGF). (Maxwell et. al., Nature, 1999, 399, 271-275).
Erythropoietin (EPO) is a naturally occurring hormone produced in response to HIFα that stimulates the production of red blood cells that carry oxygen throughout the body. EPO is usually secreted by the kidneys, and endogenous EPO increases under conditions of reduced oxygen (hypoxia). All types of anaemia are characterized by a reduced ability of the blood to carry oxygen, and are therefore accompanied by similar signs and symptoms, including paleness of the skin and mucous membranes, weakness, dizziness, fatigue, and drowsiness, resulting in a decline in quality of life. Subjects with severe anaemia showed difficulty in breathing and heart malformations. Anemia is usually associated with a condition in which the blood is deficiency in red blood cells or in hemoglobin.
Ischemic and hypoxic conditions are main causes of morbidity and mortality. Cardiovascular disease causes at least 15 million deaths each year and is the cause of 30% of deaths in the world. Among various cardiovascular diseases, ischemic heart disease and cerebrovascular disease cause about 17% of deaths. There are 1.3 million cases of non-fatal acute myocardial infarction reported each year, constituting an incidence of approximately 300 per 100,000 people. On the other hand, it is estimated that 5 million Americans suffer from venous phlebothrombosis each year, and about 600,000 of these cases cause pulmonary embolism. About one-third of patients with pulmonary embolism eventually die, making pulmonary embolism the third most common cause of death in the United States.
Currently, the treatment of ischemic and hypoxic conditions focuses on the relief of symptoms and the treatment of pathological conditions. For example, treatment of myocardial infarction includes nitroglycerin and analgesics to control pain and relieve the workload of the heart. Other medications including digoxin, diuretics, amrinone, beta-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors are used to stabilize the condition, but none of these therapies can directly act on tissue damage caused by ischemia and hypoxia.
Due to the current deficiencies in the treatment and in the production and use of recombinant EPO, there is still a need for compounds that are effective in treating erythropoietin-related conditions, such as anemia, including anemia associated with diabetes, anemia, ulcers, renal failure, cancer, infections, dialysis, surgery and chemotherapy, and conditions involving ischemia and hypoxia, such as arterial occlusive disease, angina pectoris, intestinal infarction, pulmonary infarction, cerebral ischemia, and myocardial infarction. There is also a need for compounds that effectively prevent tissue damage caused by ischemia, which occurs due to, for example, atherosclerosis, diabetes, and pulmonary disorders such as pulmonary embolism and the like. In summary, there is a need in the art for methods and compounds that modulate HIF and/or endogenous erythropoietin and that can be used to treat and prevent HIF-associated and EPO-associated disorders, including conditions associated with anaemia, ischemia, and hypoxia.